A number of different genes can be localized to the region of the chromosome 21 which is considered to be obligate for Down's Syndrome (DS) and one or more could be responsible for various aspects of the syndrome. Using animal models, it may be possible to determine the role of different genes in the phenotype. In particular, the studies included in this proposal will look at the contribution which S-100beta overexpression could make in the phenotype using an S-100beta transgenic mouse. The findings will be compared with the results in another model of DS, the TS65 Dn mouse, a segmental trisomic mouse for the distal end of chromosome 16, which contains most of the genes found on human chromosomes 21, and specifically overexpresses APP and SOD. However the, the TS65Dn mouse does not include S-100beta, which is found on chromosome 10. Since S-100beta acts as a serotoninergic growth factor and stabilizer of the neuronal cytoskeleton, and these are disrupted in DS, these are the components on the phenotype which will be examined. The investigators propose that although many genes may contribute to the phenotype of Downs syndrome, the morphologic and serotonergic changes, may be due to the over expression of S-100beta. They further propose that these changes may have behavioral consequences. This hypothesis will be tested in the S-100 beta and Ts65Dn mice in the following Specific Aims: 1.Study the morphologic development and degeneration of neurons in the hippocampus. 2 Study the development and degeneration of the serotonergic system. 3 Study any behavioral consequences in the animals, by using age appropriate behaviors. The results of these studies may lead to a clearer understanding of the role of S-100beta in DS.